tbuckley/cabot-search huggingface dataset:
Blood Vessel Organoids for Development and Disease
Authors: Kirill Salewskij, Josef M. Penninger
Journal: Circulation Research (2023)

Despite enormous advances, cardiovascular disorders are still a major threat to global health and are responsible for one-third of deaths worldwide. Research for new therapeutics and the investigation of their effects on vascular parameters is often limited by species-specific pathways and a lack of high-throughput methods. The complex 3-dimensional environment of blood vessels, intricate cellular crosstalks, and organ-specific architectures further complicate the quest for a faithful human in vitro model. The development of novel organoid models of various tissues such as brain, gut, and kidney signified a leap for the field of personalized medicine and disease research. By utilizing either embryonic- or patient-derived stem cells, different developmental and pathological mechanisms can be modeled and investigated in a controlled in vitro environment. We have recently developed self-organizing human capillary blood vessel organoids that recapitulate key processes of vasculogenesis, angiogenesis, and diabetic vasculopathy. Since then, this organoid system has been utilized as a model for other disease processes, refined, and adapted for organ specificity. In this review, we will discuss novel and alternative approaches to blood vessel engineering and explore the cellular identity of engineered blood vessels in comparison to in vivo vasculature. Future perspectives and the therapeutic potential of blood vessel organoids will be discussed.
Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial
Authors: Maha Hussain, Bertrand Tombal, Fred Saad, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Neal Shore, Evgeny Kopyltsov, Arash Rezazadeh Kalebasty, Martin Bögemann, Dingwei Ye, Felipe Cruz, Hiroyoshi Suzuki, Shivani Kapur, Shankar Srinivasan, Frank Verholen, Iris Kuss, Heikki Joensuu, Matthew R. Smith
Journal: Journal of Clinical Oncology (2023)

For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk.Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases.Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel.In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population.[Media: see text].
Quiescent Ovarian Cancer Cells Secrete Follistatin to Induce Chemotherapy Resistance in Surrounding Cells in Response to Chemotherapy
Authors: Alexander J. Cole, Santiago Panesso-Gómez, Jaynish S. Shah, Tonge Ebai, Qi Jiang, Ece Gumusoglu-Acar, Maya G. Bello, Anda Vlad, Francesmary Modugno, Robert P. Edwards, Ronald J. Buckanovich
Journal: Clinical Cancer Research (2023)

We recently reported that the transcription factor NFATC4, in response to chemotherapy, drives cellular quiescence to increase ovarian cancer chemoresistance. The goal of this work was to better understand the mechanisms of NFATC4-driven ovarian cancer chemoresistance.We used RNA sequencing to identify NFATC4-mediated differential gene expression. CRISPR-Cas9 and FST (follistatin)-neutralizing antibodies were used to assess impact of loss of FST function on cell proliferation and chemoresistance. ELISA was used to quantify FST induction in patient samples and in vitro in response to chemotherapy.We found that NFATC4 upregulates FST mRNA and protein expression predominantly in quiescent cells and FST is further upregulated following chemotherapy treatment. FST acts in at least a paracrine manner to induce a p-ATF2-dependent quiescent phenotype and chemoresistance in non-quiescent cells. Consistent with this, CRISPR knockout (KO) of FST in ovarian cancer cells or antibody-mediated neutralization of FST sensitizes ovarian cancer cells to chemotherapy treatment. Similarly, CRISPR KO of FST in tumors increased chemotherapy-mediated tumor eradication in an otherwise chemotherapy-resistant tumor model. Suggesting a role for FST in chemoresistance in patients, FST protein in the abdominal fluid of patients with ovarian cancer significantly increases within 24 hours of chemotherapy exposure. FST levels decline to baseline levels in patients no longer receiving chemotherapy with no evidence of disease. Furthermore, elevated FST expression in patient tumors is correlated with poor progression-free, post-progression-free, and overall survival.FST is a novel therapeutic target to improve ovarian cancer response to chemotherapy and potentially reduce recurrence rates.
Core binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis
Authors: Mingrui Guo, Hon Man Tim Chan, Qi-Ling Zhou, Omer An, Ying Li, Yangyang Song, Zi Hui Tan, Hui En Vanessa Ng, Philomina Sona Peramangalam, Zhi Qing Tan, Xinang Cao, Eisaku Iwanaga, Masao Matsuoka, Melissa G Ooi, Wei Ying Jen, Liang Piu Koh, Esther Chan, Lip Kun Tan, Yufen Goh, Wilson Wang, Bryan T.H. Koh, Ming Chun Chan, Melissa J. Fullwood, Wee Joo Chng, Motomi Osato, John Anto Pulikkan, Henry Yang, Leilei Chen, Daniel G. Tenen
Journal: Blood (2023)
Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor
Authors: Eliana B Gomez, Kevin Ebata, Hetal S Randeria, Mary S Rosendahl, Ernst Peder Cedervall, Tony H Morales, Lauren M Hanson, Nicholas E Brown, Xueqian Gong, Jennifer Rachelle Stephens, Wenjuan Wu, Isabel Lippincott, Karin S. Ku, Richard A Walgren, Paolo B Abada, Joshua A Ballard, Charles K Allerston, Barbara J Brandhuber
Journal: Blood (2023)

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell driven malignancies. However, approved covalent BTK inhibitors (cBTKi) are associated with treatment limitations due to off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here we describe the preclinical profile of pirtobrutinib, a potent, highly selective, non-covalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate (ATP)-binding region and shows no direct interaction with C481. As a result, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKi, prevented Y551 phosphorylation in the activation loop. These data suggest pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed pirtobrutinib was highly selective for BTK in &amp;gt;98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained &amp;gt;100-fold selectivity over other tested kinases. Collectively, these findings suggest pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical and structural attributes with the potential to treat B-cell driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.
Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy: A Prospective Multi-Centre Agreement Clinical Trial (CAN-ICE)
Authors: Marc Fortin, Moishe Liberman, Antoine Delage, Geneviève Dion, Simon Martel, Fabien Rolland, Thibaud Soumagne, Sylvain Trahan, Deborah Assayag, Elisabeth Albert, Margaret M. Kelly, Kerri A. Johannson, Zachary Guenther, Charles Leduc, Helene Manganas, Julie Prenovault, Steeve Provencher
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Transbronchial cryobiopsy (TBCB) for the diagnosis of interstitial lung disease (ILD) has shown promising results, but prospective studies with matched surgical lung biopsy (SLB) have yielded conflicting results. Objectives: We aimed to assess within- and between-center diagnostic agreement between TBCB and SLB at both the histopathologic and multidisciplinary discussion (MDD) levels in patients with diffuse ILD. Methods: In a multicenter prospective study, we performed matched TBCB and SLB in patients referred for SLB. After a blinded review by three pulmonary pathologists, all cases were reviewed by three independent ILD teams in an MDD. MDD was performed first with TBCB, then with SLB in a second session. Within-center and between-center diagnostic agreement was evaluated using percentages and correlation coefficients. Measurements and Main Results: Twenty patients were recruited and underwent contemporaneous TBCB and SLB. Within-center diagnostic agreement between TBCB-MDD and SLB-MDD was reached in 37 of the 60 (61.7%) paired observations, resulting in a Cohen's κ value of 0.46 (95% confidence interval [CI], 0.29-0.63). Diagnostic agreement increased among high-confidence or definitive diagnoses on TBCB-MDD (21 of 29 [72.4%]), but not significantly, and was more likely among cases with SLB-MDD diagnoses of idiopathic pulmonary fibrosis than fibrotic hypersensitivity pneumonitis (13 of 16 [81.2%] vs. 16 of 31 [51.6%]; P = 0.047). Between-center agreement for cases was markedly higher for SLB-MDD (κ = 0.71 [95% CI, 0.52-0.89]) than TBCB-MDD (κ = 0.29 [95% CI, 0.09-0.49]). Conclusions: This study demonstrated moderate TBCB-MDD and SLB-MDD diagnostic agreement for ILD, while between-center agreement was fair for TBCB-MDD and substantial for SLB-MDD. Clinical trial registered with www.clinicaltrials.gov (NCT02235779).
A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary Disease
Authors: Samir Rustam, Yang Hu, Seyed Babak Mahjour, Andre F. Rendeiro, Hiranmayi Ravichandran, Andreacarola Urso, Frank D’Ovidio, Fernando J. Martinez, Nasser K. Altorki, Bradley Richmond, Vasiliy Polosukhin, Jonathan A. Kropski, Timothy S. Blackwell, Scott H. Randell, Olivier Elemento, Renat Shaykhiev
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown. Objectives: To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin. Methods: We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air–liquid interface model. Measurements and Main Results: The atlas of cellular heterogeneity along the proximal–distal axis of the human lung was assembled and identified region-specific cellular states, including SCGB3A2+ SFTPB+ terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8+ T cells normally enriched in proximal airways, and augmented IFN-γ signaling. Basal cells residing in pre-TBs/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-γ. Conclusions: Altered maintenance of the unique cellular organization of pre-TBs/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD.
Tissue-Resident Memory T Cells Are Implicated in the Pathogenesis of Hypersensitivity Pneumonitis
Authors: Wezi Sendama, Wendy Funston, Anthony J. Rostron, A. John Simpson
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Tissue-Resident Memory T Cells Are Implicated in the Pathogenesis of Hypersensitivity Pneumonitis." American Journal of Respiratory and Critical Care Medicine, 207(9), pp. 1246–1249
2023 ACC/AHA/SCAI Advanced Training Statement on Interventional Cardiology (Coronary, Peripheral Vascular, and Structural Heart Interventions)
Authors: Theodore A. Bass, J. Dawn Abbott, Ehtisham Mahmud, Sahil A. Parikh, Jamil Aboulhosn, Mahi L. Ashwath, Bryan Baranowski, Lisa Bergersen, Hannah I. Chaudry, Megan Coylewright, Ali E. Denktas, Kamal Gupta, J. Antonio Gutierrez, Jonathan Haft, Beau M. Hawkins, Howard C. Herrmann, Navin K. Kapur, Sena Kilic, John Lesser, C. Huie Lin, Rodrigo Mendirichaga, Vuyisile T. Nkomo, Linda G. Park, Dawn R. Phoubandith, Nishath Quader, Michael W. Rich, Kenneth Rosenfield, Saher S. Sabri, Murray L. Shames, Stanton K. Shernan, Kimberly A. Skelding, Jacqueline Tamis-Holland, Vinod H. Thourani, Jennifer A. Tremmel, Seth Uretsky, Jessica Wageman, Frederick Welt, Brian K. Whisenant, Christopher J. White, Celina M. Yong
Journal: Journal of the American College of Cardiology (2023)
Neoadjuvant chemoradiotherapy with radiation dose escalation with contact x-ray brachytherapy boost or external beam radiotherapy boost for organ preservation in early cT2–cT3 rectal adenocarcinoma (OPERA): a phase 3, randomised controlled trial
Authors: Jean-Pierre Gerard, Nicolas Barbet, Renaud Schiappa, Nicolas Magné, Isabelle Martel, Laurent Mineur, Mélanie Deberne, Thomas Zilli, Amandeep Dhadda, Arthur Sun Myint
Journal: The Lancet. Gastroenterology & hepatology (2023)
Evidence of widespread endemic populations of highly multidrug resistant Klebsiella pneumoniae in hospital settings in Hanoi, Vietnam: a prospective cohort study
Authors: My H Pham, Le Thi Hoi, Mathew A Beale, Fahad A Khokhar, Nguyen Thi Hoa, Patrick Musicha, Grace A Blackwell, Hoang Bao Long, Dang Thi Huong, Nguyen Gia Binh, Dao Xuan Co, Tran Giang, Cuong Bui, Hai Ninh Tran, James Bryan, Archie Herrick, Theresa Feltwell, Behzad Nadjm, Julian Parkhill, Hindrik Rogier van Doorn, Nguyen Vu Trung, Nguyen Van Kinh, Mili Estée Török, Nicholas R Thomson
Journal: The Lancet Microbe (2023)
Patient-level and system-level determinants of stroke fatality across 16 large hospitals in Ghana and Nigeria: a prospective cohort study
Authors: Fred S Sarfo, Onoja M Akpa, Bruce Ovbiagele, Albert Akpalu, Kolawole Wahab, Reginald Obiako, Morenikeji Komolafe, Lukman Owolabi, Godwin Ogbole, Adekunle Fakunle, Akinkunmi Paul Okekunle, Osahon J Asowata, Benedict Calys-Tagoe, Ezinne O Uvere, Taofeek Sanni, Samuel Olowookere, Philip Ibinaiye, Joshua O Akinyemi, Oyedunni Arulogun, Carolyn Jenkins, Daniel T Lackland, Hemant K Tiwari, Suleiman Y Isah, Sani A Abubakar, Adebayo Oladimeji, Philip Adebayo, Josephine Akpalu, Ugochukwu Onyeonoro, James A Ogunmodede, Cynthia Akisanya, Yaw Mensah, Olalekan I Oyinloye, Lambert Appiah, Atinuke M Agunloye, Godwin O Osaigbovo, Abiodun M Adeoye, Osimhiarherhuo Ohifemen Adeleye, Ruth Y Laryea, Taiwo Olunuga, Okechukwu S Ogah, Wisdom Oguike, Mayowa Ogunronbi, Wasiu Adeniyi, Obiabo Y Olugbo, Abiodun H Bello, Luqman Ogunjimi, Samuel Diala, Hamisu A Dambatta, Arti Singh, Sheila Adamu, Vida Obese, Nathaniel Adusei, Dorcas Owusu, Michael Ampofo, Raelle Tagge, Bimbo Fawale, Joseph Yaria, Rufus O Akinyemi, Mayowa O Owolabi
Journal: The Lancet Global Health (2023)
DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis
Authors: Kazufumi Kunimura, Sayaka Akiyoshi, Takehito Uruno, Keisuke Matsubara, Daiji Sakata, Kenji Morino, Kenichiro Hirotani, Yoshinori Fukui
Journal: Journal of Allergy and Clinical Immunology (2023)
Type 2 inflammation drives an airway basal stem cell program through insulin receptor substrate signaling
Authors: Xin Wang, Nils R. Hallen, Minkyu Lee, Sachin Samuchiwal, Qihua Ye, Kathleen M. Buchheit, Alice Z. Maxfield, Rachel E. Roditi, Regan W. Bergmark, Neil Bhattacharyya, Tessa Ryan, Deb Gakpo, Soumya Raychaudhuri, Dan Dwyer, Tanya M. Laidlaw, Joshua A. Boyce, Maria Gutierrez-Arcelus, Nora A. Barrett
Journal: Journal of Allergy and Clinical Immunology (2023)
Axial and radial axonal diffusivities and radii from single encoding strongly diffusion-weighted MRI
Authors: Marco Pizzolato, Erick Jorge Canales-Rodríguez, Mariam Andersson, Tim B. Dyrby
Journal: Medical Image Analysis (2023)

We enable the estimation of the per-axon axial diffusivity from single encoding, strongly diffusion-weighted, pulsed gradient spin echo data. Additionally, we improve the estimation of the per-axon radial diffusivity compared to estimates based on spherical averaging. The use of strong diffusion weightings in magnetic resonance imaging (MRI) allows to approximate the signal in white matter as the sum of the contributions from only axons. At the same time, spherical averaging leads to a major simplification of the modeling by removing the need to explicitly account for the unknown distribution of axonal orientations. However, the spherically averaged signal acquired at strong diffusion weightings is not sensitive to the axial diffusivity, which cannot therefore be estimated although needed for modeling axons - especially in the context of multi-compartmental modeling. We introduce a new general method for the estimation of both the axial and radial axonal diffusivities at strong diffusion weightings based on kernel zonal modeling. The method could lead to estimates that are free from partial volume bias with gray matter or other isotropic compartments. The method is tested on publicly available data from the MGH Adult Diffusion Human Connectome project. We report reference values of axonal diffusivities based on 34 subjects, and derive estimates of axonal radii from only two shells. The estimation problem is also addressed from the angle of the required data preprocessing, the presence of biases related to modeling assumptions, current limitations, and future possibilities.
Development and Validation of a Prediction Model for Kidney Failure in Long-Term Survivors of Childhood Cancer
Authors: Natalie L. Wu, Yan Chen, Bryan V. Dieffenbach, Matthew J. Ehrhardt, Sangeeta Hingorani, Rebecca M. Howell, John L. Jefferies, Daniel A. Mulrooney, Kevin C. Oeffinger, Leslie L. Robison, Brent R. Weil, Yan Yuan, Yutaka Yasui, Melissa M. Hudson, Wendy M. Leisenring, Gregory T. Armstrong, Eric J. Chow
Journal: Journal of Clinical Oncology (2023)

Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer.
Alliance of Heart and Endoderm: Multilineage Organoids to Model Co-development
Authors: Wai Hoe Ng, Barbie Varghese, Hongpeng Jia, Xi Ren
Journal: Circulation Research (2023)

Studies in animal models tracing organogenesis of the mesoderm-derived heart have emphasized the importance of signals coming from adjacent endodermal tissues in coordinating proper cardiac morphogenesis. Although in vitro models such as cardiac organoids have shown great potential to recapitulate the physiology of the human heart, they are unable to capture the complex crosstalk that takes place between the co-developing heart and endodermal organs, partly due to their distinct germ layer origins. In an effort to address this long-sought challenge, recent reports of multilineage organoids comprising both cardiac and endodermal derivatives have energized the efforts to understand how inter-organ, cross-lineage communications influence their respective morphogenesis. These co-differentiation systems have produced intriguing findings of shared signaling requirements for inducing cardiac specification together with primitive foregut, pulmonary, or intestinal lineages. Overall, these multilineage cardiac organoids offer an unprecedented window into human development that can reveal how the endoderm and heart cooperate to direct morphogenesis, patterning, and maturation. Further, through spatiotemporal reorganization, the co-emerged multilineage cells self-assemble into distinct compartments as seen in the cardiac-foregut, cardiac-intestine, and cardiopulmonary organoids and undergo cell migration and tissue reorganization to establish tissue boundaries. Looking into the future, these cardiac incorporated, multilineage organoids will inspire future strategies for improved cell sourcing for regenerative interventions and provide more effective models for disease investigation and drug testing. In this review, we will introduce the developmental context of coordinated heart and endoderm morphogenesis, discuss strategies for in vitro co-induction of cardiac and endodermal derivatives, and finally comment on the challenges and exciting new research directions enabled by this breakthrough.
VP1-2023: Pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: Phase III KEYNOTE-859 study
Authors: S.Y. Rha, L.S. Wyrwicz, P.E.Y. Weber, Y. Bai, M.H. Ryu, J. Lee, F. Rivera, G.V. Alves, M. Garrido, K-K. Shiu, M. González Fernández, J. Li, M. Lowery, T. Cil, F.J.S.M. Cruz, S. Qin, L. Yin, S. Bordia, P. Bhagia, D-Y. Oh
Journal: Annals of Oncology (2023)